Fine resolution identification of a neural fulcrum for the treatment of chronic cardiac dysfunction

ABSTRACT

Systems and methods are provided for delivering neurostimulation therapies to patients for treating chronic heart failure. A neural fulcrum zone is identified and ongoing neurostimulation therapy is delivered within the neural fulcrum zone. This neural fulcrum zone may be identified by monitoring a patient&#39;s response to incrementally increased intensity settings at a first frequency. If the incremental intensity increases do not result in the identification of the neural fulcrum zone, the frequency may be changed to provide finer resolution identification of the neural fulcrum zone.

FIELD

This application relates to neuromodulation.

BACKGROUND

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction and eventual patient death. CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF. Forinstance, VNS has been demonstrated in canine studies as efficacious insimulated treatment of AF and heart failure, such as described in Zhanget al., “Chronic Vagus Nerve Stimulation Improves Autonomic Control andAttenuates Systemic Inflammation and Heart Failure Progression in aCanine High-Rate Pacing Model,” Circ Heart Fail 2009, 2, pp. 692-699(Sep. 22, 2009), the disclosure of which is incorporated by reference.The results of a multi-center open-label phase II study in which chronicVNS was utilized for CHF patients with severe systolic dysfunction isdescribed in De Ferrari et al., “Chronic Vagus Nerve Stimulation: A Newand Promising Therapeutic Approach for Chronic Heart Failure,” EuropeanHeart Journal, 32, pp. 847-855 (Oct. 28, 2010).

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under a control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's sideeffect threshold gradually increases, allowing for an increase inintensity during subsequent titration sessions.

Conventional general therapeutic alteration of cardiac vagal efferentactivation through electrical stimulation targets only the efferentnerves of the parasympathetic nervous system, such as described inSabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,”Heart Fail. Rev., 16:171-178 (2011), the disclosure of which isincorporated by reference. The Sabbah paper discusses canine studiesusing a vagus nerve stimulation system, manufactured by BioControlMedical Ltd., Yehud, Israel, which includes an electrical pulsegenerator, right ventricular endocardial sensing lead, and right vagusnerve cuff stimulation lead. The sensing lead enables stimulation of theright vagus nerve in a highly specific manner, which includesclosed-loop synchronization of the vagus nerve stimulation pulse to thecardiac cycle. An asymmetric tri-polar nerve cuff electrode is implantedon the right vagus nerve at the mid-cervical position. The electrodeprovides cathodic induction of action potentials while simultaneouslyapplying asymmetric anodal block that lead to preferential activation ofvagal efferent fibers. Electrical stimulation of the right cervicalvagus nerve is delivered only when heart rate is above a presetthreshold. Stimulation is provided at an intensity intended to reducebasal heart rate by ten percent by preferential stimulation of efferentvagus nerve fibers leading to the heart while blocking afferent neuralimpulses to the brain. Although effective in partially restoringbaroreflex sensitivity, increasing left ventricular ejection fraction,and decreasing left ventricular end diastolic and end systolic volumes,a portion of the therapeutic benefit is due to incidental recruitment ofafferent parasympathetic nerve fibers in the vagus. Efferent stimulationalone is less effective than bidirectional stimulation at restoringautonomic balance.

Accordingly, a need remains for an approach to efficiently providingneurostimulation therapy, and, in particular, to neurostimulationtherapy for treating chronic cardiac dysfunction and other conditions.

SUMMARY

In accordance with embodiments of the present invention, a neuralfulcrum zone is identified, and ongoing neurostimulation therapy isdelivered within the neural fulcrum zone. This neural fulcrum zonecorresponds to a combination of stimulation parameters at whichautonomic engagement is achieved, while the tachycardia-inducingstimulation effects are offset by the bradycardia-inducing effects,thereby minimizing side effects such as significant heart rate changeswhile providing a therapeutic level of stimulation. The neural fulcrumzone may be identified by monitoring a patient's response toincrementally increased intensity settings at a first frequency. If theincremental intensity increases do not result in the identification ofthe neural fulcrum zone, the frequency may be changed to provide finerresolution identification of the neural fulcrum zone.

In accordance with embodiments of the present invention, a method ofoperating an implantable medical device (IMD) comprising aneurostimulator coupled to an electrode assembly, said neurostimulatoradapted to deliver a stimulation signal at a plurality of intensityparameter levels at predefined increments is provided. The methodcomprises: monitoring a parameter indicative of the autonomic balance orautonomic engagement of a patient implanted with the IMD, such as, forexample, heart rate; delivering to the patient a first set ofstimulation signals at a first frequency, wherein said deliveringcomprises incrementally increasing the intensity parameter level by thepredefined increment for subsequent stimulation signals untilbradycardia is detected; wherein if tachycardia is detected in responseto the stimulation signal having an intensity parameter level onepredefined increment below the intensity parameter level at whichbradycardia is detected, delivering to the patient a second set ofstimulation signals at a second frequency lower than the firstfrequency, wherein said delivering the second set of stimulation signalscomprises incrementally increasing the intensity parameter level by thepredefined increment for subsequent stimulation signals untilbradycardia is detected; wherein if a transition heart rate response isdetected in response to the stimulation signal having an intensityparameter level one predefined increment below the intensity parameterlevel at which bradycardia is detected, identifying the stimulationsignal resulting in the transition heart rate response as correspondingto a neural fulcrum zone.

In accordance with embodiments of the present invention, a method ofoperating an IMD comprising a neurostimulator coupled to an electrodeassembly, said neurostimulator adapted to deliver a stimulation signalat a plurality of intensity parameter levels at predefined increments isprovided. The method comprises: monitoring a heart rate of a patientimplanted with the IMD; delivering to the patient a first set ofstimulation signals at a first frequency, wherein said deliveringcomprises incrementally increasing the intensity parameter level by thepredefined increment for subsequent stimulation signals until eitherbradycardia or a transition heart rate response is detected; wherein iftachycardia is detected in response to the stimulation signal having anintensity parameter level one predefined increment below the intensityparameter level at which bradycardia is detected, delivering to thepatient a second set of stimulation signals at a second frequency lowerthan the first frequency, wherein said delivering the second set ofstimulation signals comprises incrementally increasing the intensityparameter level by the predefined increment until either bradycardia ora transition heart rate response is detected; and when the transitionheart rate response is detected, identifying the stimulation signalresulting in the transition heart rate response as corresponding to aneural fulcrum zone.

In accordance with embodiments of the present invention, aneurostimulation system is provided, including: an implantable medicaldevice (IMD) comprising a neurostimulator coupled to an electrodeassembly, said neurostimulator adapted to deliver a stimulation signalto a patient; and a control system programmed to: monitor a heart rateof a patient implanted with the IMD; activate the IMD to deliver to thepatient a first set of stimulation signals at a first frequency, whereinsaid delivery comprises incrementally increasing the intensity parameterlevel by the predefined increment for subsequent stimulation signalsuntil bradycardia is detected; wherein if tachycardia is detected inresponse to the stimulation signal having an intensity parameter levelone predefined increment below the intensity parameter level at whichbradycardia is detected, activate the IMD to deliver to the patient asecond set of stimulation signals at a second frequency lower than thefirst frequency, wherein said delivery of the second set of stimulationsignals comprises incrementally increasing the intensity parameter levelby the predefined increment for subsequent stimulation signals untilbradycardia is detected; wherein if a transition heart rate response isdetected in response to the stimulation signal having an intensityparameter level one predefined increment below the intensity parameterlevel at which bradycardia is detected, identifying the stimulationsignal resulting in the transition heart rate response as correspondingto a neural fulcrum zone.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 3.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIGS. 8A-8C are illustrative charts reflecting a heart rate response togradually increased stimulation intensity at different frequencies.

FIG. 9 illustrates a method of operating an implantable medical devicecomprising neurostimulator coupled to an electrode assembly.

FIG. 10 is an illustrative chart reflecting a heart rate response togradually increased stimulation intensity delivered by an implanted VNSsystem at two different frequencies.

DETAILED DESCRIPTION

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers, and both afferent and efferent fibers. Thesefibers have different diameters and myelination, and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1) in a male patient 10, in accordance with embodiments of thepresent invention. The VNS provided through the stimulation system 11operates under several mechanisms of action. These mechanisms includeincreasing parasympathetic outflow and inhibiting sympathetic effects byinhibiting norepinephrine release and adrenergic receptor activation.More importantly, VNS triggers the release of the endogenousneurotransmitter acetylcholine and other peptidergic substances into thesynaptic cleft, which has several beneficial anti-arrhythmic,anti-apoptotic, and anti-inflammatory effects as well as beneficialeffects at the level of the central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The stimulating nerve electrode assembly 125, preferablycomprising at least an electrode pair, is conductively connected to thedistal end of an insulated, electrically conductive lead assembly 13 andelectrodes 14. The electrodes 14 may be provided in a variety of forms,such as, e.g., helical electrodes, probe electrodes, cuff electrodes, aswell as other types of electrodes. The implantable vagus stimulationsystem 11 can be remotely accessed following implant through an externalprogrammer, such as the programmer 40 shown in FIG. 3 and described infurther detail below. The programmer 40 can be used by healthcareprofessionals to check and program the neurostimulator 12 afterimplantation in the patient 10. In some embodiments, an external magnetmay provide basic controls, such as described in commonly assigned U.S.Pat. No. 8,600,505, entitled “Implantable Device For FacilitatingControl Of Electrical Stimulation Of Cervical Vagus Nerves For TreatmentOf Chronic Cardiac Dysfunction,” the disclosure of which is incorporatedby reference. For further example, an electromagnetic controller mayenable the patient 10 or healthcare professional to interact with theimplanted neurostimulator 12 to exercise increased control over therapydelivery and suspension, such as described in commonly-assigned U.S.Pat. No. 8,571,654, entitled “Vagus Nerve Neurostimulator With MultiplePatient-Selectable Modes For Treating Chronic Cardiac Dysfunction,” thedisclosure of which is incorporated by reference. For further example,an external programmer may communicate with the neurostimulation system11 via other wired or wireless communication methods, such as, e.g.,wireless RF transmission. Together, the implantable vagus stimulationsystem 11 and one or more of the external components form a VNStherapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively or in other various combinations. Stimulation may bethrough multimodal application of continuously-cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. A study of the relationship between cardiac autonomic nerveactivity and blood pressure changes in ambulatory dogs is described inJ. Hellyer et al., “Autonomic Nerve Activity and Blood Pressure inAmbulatory Dogs,” Heart Rhythm, Vol. 11(2), pp. 307-313 (February 2014).Generally, cervical vagus nerve stimulation results in propagation ofaction potentials from the site of stimulation in a bi-directionalmanner. The application of bi-directional propagation in both afferentand efferent directions of action potentials within neuronal fiberscomprising the cervical vagus nerve improves cardiac autonomic balance.Afferent action potentials propagate toward the parasympathetic nervoussystem's origin in the medulla in the nucleus ambiguus, nucleus tractussolitarius, and the dorsal motor nucleus, as well as towards thesympathetic nervous system's origin in the intermediolateral cell columnof the spinal cord. Efferent action potentials propagate toward theheart 17 to activate the components of the heart's intrinsic nervoussystem. Either the left or right vagus nerve 15, 16 can be stimulated bythe stimulation system 11. The right vagus nerve 16 has a moderatelylower (approximately 30%) stimulation threshold than the left vagusnerve 15 for heart rate effects at the same stimulation frequency andpulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy DemiPulse Model 103or AspireSR Model 106 pulse generator, manufactured and sold byCyberonics, Inc., Houston, Tex., although other manufactures and typesof implantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PerenniaDURAModel 303 lead, or PerenniaFLEX Model 304 lead, also manufactured andsold by Cyberonics, Inc., in two sizes based, for example, on a helicalelectrode inner diameter, although other manufactures and types ofsingle-pin receptacle-compatible therapy leads and electrodes could alsobe used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to delivercontinuously-cycling, intermittent and periodic ON-OFF cycles of VNS.Such delivery produces action potentials in the underlying nerves thatpropagate bi-directionally.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible, implantation-safematerial, such as titanium. The housing 21 contains electronic circuitry22 powered by a battery 23, such as a lithium carbon monofluorideprimary battery or a rechargeable secondary cell battery. The electroniccircuitry 22 may be implemented using complementary metal oxidesemiconductor integrated circuits that include a microprocessorcontroller that executes a control program according to storedstimulation parameters and timing cycles; a voltage regulator thatregulates system power; logic and control circuitry, including arecordable memory 29 within which the stimulation parameters are stored,that controls overall pulse generator function, receives and implementsprogramming commands from the external programmer, or other externalsource, collects and stores telemetry information, processes sensoryinput, and controls scheduled and sensory-based therapy outputs; atransceiver that remotely communicates with the external programmerusing radio frequency signals; an antenna, which receives programminginstructions and transmits the telemetry information to the externalprogrammer; and a reed switch 30 that provides remote access to theoperation of the neurostimulator 12 using an external programmer, asimple patient magnet, or an electromagnetic controller. The recordablememory 29 can include both volatile (dynamic) and persistent (static)forms of memory, such as firmware within which the stimulationparameters and timing cycles can be stored. Other electronic circuitryand components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 internally includes a lead connector block (not shown) and aset of screws 26.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an ECG-type electrode.Through the electrode, the patient's heart beat can be sensed bydetecting ventricular depolarization. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for cardiacphysiological measures, for instance, detection of the P-wave, QRScomplex, and T-wave. The heart rate sensor 31 provides the sensed heartrate to the control and logic circuitry as sensory inputs that can beused to determine the onset or presence of arrhythmias, particularly VT,and/or to monitor and record changes in the patient's heart rate overtime or in response to applied stimulation signals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28. During implantation, the connector pin 28 isguided through the receptacle 25 into the header 24 and securelyfastened in place using the set screws 26 to electrically couple thelead assembly 13 to the neurostimulator 12. On a distal end, the leadassembly 13 terminates with the electrode 14, which bifurcates into apair of anodic and cathodic electrodes 62 (as further described infrawith reference to FIG. 4). In one embodiment, the lead connector 27 ismanufactured using silicone and the connector pin 28 is made ofstainless steel, although other suitable materials could be used, aswell. The insulated lead body 13 utilizes a silicone-insulated alloyconductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes. Thepolarity of the electrodes could be configured into a monopolar cathode,a proximal anode and a distal cathode, or a proximal cathode and adistal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters, suchas described in commonly-assigned U.S. Pat. Nos. 8,600,505 and8,571,654, cited supra. FIG. 3 is a diagram showing an externalprogrammer 40 for use with the implantable neurostimulator 12 of FIG. 1.The external programmer 40 includes a healthcare provider operableprogramming computer 41 and a programming wand 42. Generally, use of theexternal programmer is restricted to healthcare providers, while morelimited manual control is provided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42 and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. In oneembodiment, the programming computer is a tablet computer that mayoperate under the iOS operating system from Apple Inc., such as the iPadfrom Apple Inc., or may operate under the Android operating system fromGoogle Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd.In an alternative embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC,Windows Mobile, Windows Phone, Windows RT, or Windows operating systems,licensed by Microsoft Corporation, Redmond, Wash., such as the Surfacefrom Microsoft Corporation, the Dell Axim X5 and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. The programming computer 41 may further beconfigured to receive inputs, such as physiological signals receivedfrom patient sensors (e.g., implanted or external). These sensors may beconfigured to monitor one or more physiological signals, e.g., vitalsigns, such as body temperature, pulse rate, respiration rate, bloodpressure, etc. These sensors may be coupled directly to the programmingcomputer 41 or may be coupled to another instrument or computing devicewhich receives the sensor input and transmits the input to theprogramming computer 41. The programming computer 41 may monitor,record, and/or respond to the physiological signals in order toeffectuate stimulation delivery in accordance with embodiments of thepresent invention.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

Preferably, the electrodes 14 are helical and placed on the cervicalvagus nerve 15, 16 at the location below where the superior and inferiorcardiac branches separate from the cervical vagus nerve. FIG. 4 is adiagram showing the helical electrodes 14 provided as on the stimulationlead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16 in situ 50.Although described with reference to a specific manner and orientationof implantation, the specific surgical approach and implantation siteselection particulars may vary, depending upon physician discretion andpatient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a monopolar cathode, aproximal anode and a distal cathode, or a proximal cathode and a distalanode. In addition, an anchor tether 53 is fastened over the lead bodies57, 58 that maintains the helical electrodes' position on the vagusnerve 61 following implant. In one embodiment, the conductors of theelectrodes 51, 52 are manufactured using a platinum and iridium alloy,while the helical materials of the electrodes 51, 52 and the anchortether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. Patent application entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7,2011, published as U.S. Patent Publication no. 2013-0158618 A1, pending,the disclosure of which is incorporated by reference.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously-cycling, intermittent andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly-assignedU.S. Pat. No. 8,577,458, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S.Patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. Patentapplication entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, U.S. PatentPublication No. 2013-0158616 A1, pending, and U.S. Patent applicationentitled “Implantable Device for Providing Electrical Stimulation ofCervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction withBounded Titration,” Ser. No. 13/314,135, filed on Dec. 7, 2011, U.S.Patent Publication No. 2013-0158617 A1, pending, the disclosures ofwhich are incorporated by reference. Finally, the neurostimulator 12 canbe used to counter natural circadian sympathetic surge upon awakeningand manage the risk of cardiac arrhythmias during or attendant to sleep,particularly sleep apneic episodes, such as respectively described incommonly-assigned U.S. Patent application entitled “ImplantableNeurostimulator-Implemented Method For Enhancing Heart Failure PatientAwakening Through Vagus Nerve Stimulation,” Ser. No. 13/673,811, filedon Nov. 9, 2012, pending, the disclosure of which is incorporated byreference.

The VNS stimulation signal may be delivered as a therapy in amaintenance dose having an intensity that is insufficient to elicitundesirable side effects, such as cardiac arrhythmias. The VNS can bedelivered with a periodic duty cycle in the range of 2% to 89% with apreferred range of around 4% to 36% that is delivered as a low intensitymaintenance dose. Alternatively, the low intensity maintenance dose maycomprise a narrow range approximately at 17.5%, such as around 15% to20%. The selection of duty cycle is a tradeoff among competing medicalconsiderations. The duty cycle is determined by dividing the stimulationON time by the sum of the ON and OFF times of the neurostimulator 12during a single ON-OFF cycle. However, the stimulation time may alsoneed to include ramp-up time and ramp-down time, where the stimulationfrequency exceeds a minimum threshold (as further described infra withreference to FIG. 7).

FIG. 5 is a graph 70 showing, by way of example, the relationshipbetween the targeted therapeutic efficacy 73 and the extent of potentialside effects 74 resulting from use of the implantable neurostimulator 12of FIG. 1, after the patient has completed the titration process. Thegraph in FIG. 5 provides an illustration of the failure of increasedstimulation intensity to provide additional therapeutic benefit, oncethe stimulation parameters have reached the neural fulcrum zone, as willbe described in greater detail below with respect to FIG. 8. As shown inFIG. 5, the x-axis represents the duty cycle 71. The duty cycle isdetermined by dividing the stimulation ON time by the sum of the ON andOFF times of the neurostimulator 12 during a single ON-OFF cycle.However, the stimulation time may also include ramp-up time andramp-down time, where the stimulation frequency exceeds a minimumthreshold (as further described infra with reference to FIG. 7). They-axis represents physiological response 72 to VNS therapy. Thephysiological response 72 can be expressed quantitatively for a givenduty cycle 71 as a function of the targeted therapeutic efficacy 73 andthe extent of potential side effects 74, as described infra. The maximumlevel of physiological response 72 (“max”) signifies the highest pointof targeted therapeutic efficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 73 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 73,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 73 steeply increases beginning at around a 5% duty cycle, andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents one optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over stimulation time plus inhibition time. The y-axisrepresents therapeutic points 82 reached in operating theneurostimulator 12 at a given duty cycle 81. The optimal duty range 83is a function 84 of the intersection 75 of the targeted therapeuticefficacy 73 and the extent of potential side effects 74. The therapeuticoperating points 82 can be expressed quantitatively for a given dutycycle 81 as a function of the values of the targeted therapeuticefficacy 73 and the extent of potential side effects 74 at their pointof intersection in the graph 70 of FIG. 5. The optimal therapeuticoperating point 85 (“max”) signifies a tradeoff that occurs at the pointof highest targeted therapeutic efficacy 73 in light of lowest potentialside effects 74 and that point will typically be found within the rangeof a 5% to 30% duty cycle 81. Other expressions of duty cycles andrelated factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, VNS is delivered in a lowlevel maintenance dose that uses alternating cycles of stimuliapplication (ON) and stimuli inhibition (OFF) that are tuned to activateboth afferent and efferent pathways. Stimulation results inparasympathetic activation and sympathetic inhibition, both throughcentrally-mediated pathways and through efferent activation ofpreganglionic neurons and local circuit neurons. FIG. 7 is a timingdiagram showing, by way of example, a stimulation cycle and aninhibition cycle of VNS 90, as provided by implantable neurostimulator12 of FIG. 1. The stimulation parameters enable the electricalstimulation pulse output by the neurostimulator 12 to be varied by bothamplitude (output current 96) and duration (pulse width 94). The numberof output pulses delivered per second determines the signal frequency93. In one embodiment, a pulse width in the range of 100 to 250 μSecdelivers between 0.02 mA and 50 mA of output current at a signalfrequency of about 10 Hz, although other therapeutic values could beused as appropriate. In general, the stimulation signal delivered to thepatient may be defined by a stimulation parameter set comprising atleast an amplitude, a frequency, a pulse width, and a duty cycle.

In one embodiment, the stimulation time is considered the time periodduring which the neurostimulator 12 is ON and delivering pulses ofstimulation, and the OFF time is considered the time period occurringin-between stimulation times during which the neurostimulator 12 is OFFand inhibited from delivering stimulation.

In another embodiment, as shown in FIG. 7, the neurostimulator 12implements a stimulation time 91 comprising an ON time 92, a ramp-uptime 97 and a ramp-down time 98 that respectively precede and follow theON time 92. Under this embodiment, the ON time 92 is considered to be atime during which the neurostimulator 12 is ON and delivering pulses ofstimulation at the full output current 96. Under this embodiment, theOFF time 95 is considered to comprise the ramp-up time 97 and ramp-downtime 98, which are used when the stimulation frequency is at least 10Hz, although other minimum thresholds could be used, and both ramp-upand ramp-down times 97, 98 last two seconds, although other time periodscould also be used. The ramp-up time 97 and ramp-down time 98 allow thestrength of the output current 96 of each output pulse to be graduallyincreased and decreased, thereby avoiding deleterious reflex behaviordue to sudden delivery or inhibition of stimulation at a programmedintensity.

Therapeutic vagus neural stimulation has been shown to providecardioprotective effects. Although delivered in a maintenance dosehaving an intensity that is insufficient to elicit undesirable sideeffects, such as cardiac arrhythmias, ataxia, coughing, hoarseness,throat irritation, voice alteration, or dyspnea, therapeutic VNS cannevertheless potentially ameliorate pathological tachyarrhythmias insome patients. Although VNS has been shown to decrease defibrillationthreshold, VNS has not been shown to terminate VF in the absence ofdefibrillation. VNS prolongs ventricular action potential duration, somay be effective in terminating VT. In addition, the effect of VNS onthe AV node may be beneficial in patients with AF by slowing conductionto the ventricles and controlling ventricular rate.

Neural Fulcrum Zone

As described above, autonomic regulation therapy results in simultaneouscreation and propagation of efferent and afferent action potentialswithin nerve fibers comprising the cervical vagus nerve. Uponstimulation of the cervical vagus nerve, action potentials propagateaway from the stimulation site in two directions, efferently toward theheart and afferently toward the brain. Different parameter settings forthe neurostimulator 12 may be adjusted to deliver varying stimulationintensities to the patient. The various stimulation parameter settingsfor current VNS devices include output current amplitude, signalfrequency, pulse width, signal ON time, and signal OFF time.

When delivering neurostimulation therapies to patients, it is generallydesirable to avoid stimulation intensities that result in eitherexcessive tachycardia or excessive bradycardia. However, researchershave typically utilized the patient's heart rate changes as an indicatorof effective recruitment of nerve fibers and engagement of the autonomicnervous system, which is indicative of therapeutic efficacy. Someresearchers have proposed that heart rate reduction caused by VNSstimulation is itself beneficial to the patient.

In accordance with embodiments of the present invention, a neuralfulcrum zone is identified, and neurostimulation therapy is deliveredwithin the neural fulcrum zone. This neural fulcrum zone corresponds toa combination of stimulation parameters at which autonomic engagement isachieved, while the tachycardia-inducing stimulation effects are offsetby the bradycardia-inducing effects, thereby minimizing side effectssuch as significant heart rate changes while providing a therapeuticlevel of stimulation One method of identifying the neural fulcrum zoneis by delivering a plurality of stimulation signals at a fixed frequencybut with one or more other parameter settings changed so as to graduallyincrease the intensity of the stimulation.

FIGS. 8A-8C provide illustrative charts reflecting the location of theneural fulcrum zone. FIG. 8A is a chart 800 illustrating a heart rateresponse in response to such a gradually increased intensity at a firstfrequency, in accordance with embodiments of the present invention. Inthis chart 800, the x-axis represents the intensity level of thestimulation signal, and the y-axis represents the observed heart ratechange from the patient's baseline basal heart rate observed when nostimulation is delivered. In this example, the stimulation intensity isincreased by increasing the output current amplitude.

A first set 810 of stimulation signals is delivered at a first frequency(e.g., 10 Hz). Initially, as the intensity (e.g., output currentamplitude) is increased, a tachycardia zone 851-1 is observed, duringwhich period, the patient experiences a mild tachycardia. As theintensity continues to be increased for subsequent stimulation signals,the patient's heart rate response begins to decrease and eventuallyenters a bradycardia zone 853-1, in which a bradycardia response isobserved in response to the stimulation signals. As described above, theneural fulcrum zone is a range of stimulation parameters at which thefunctional effects from afferent activation are balanced with theeffects from efferent activation to avoid extreme heart rate changeswhile providing therapeutic levels of stimulation intensity. Inaccordance with some embodiments, the neural fulcrum zone 852-1 can belocated by identifying the zone in which the patient's response tostimulation produces either no heart rate change or a mildly decreasedheart rate change (e.g., 5% decrease, or a target number of beats perminute). As the intensity of stimulation is further increased at thefixed first frequency, the patient enters an undesirable bradycardiazone 853-1. In these embodiments, the patient's heart rate response isused as an indicator of autonomic engagement. In other embodiments,other physiological responses may be used to indicate the zone ofautonomic engagement at which the propagation of efferent and afferentaction potentials are balanced.

FIG. 8B is a chart 860 illustrating a heart rate response in response tosuch a gradually increased intensity at two additional frequencies, inaccordance with embodiments of the present invention. In this chart 860,the x-axis and y-axis represent the intensity level of the stimulationsignal and the observed heart rate change, respectively, as in FIG. 8A,and the first set 810 of stimulation signals from FIG. 8A is also shown.

A second set 810 of stimulation signals is delivered at a secondfrequency lower than the first frequency (e.g., 5 Hz). Initially, as theintensity (e.g., output current amplitude) is increased, a tachycardiazone 851-2 is observed, during which period, the patient experiences amild tachycardia. As the intensity continues to be increased forsubsequent stimulation signals, the patient's heart rate response beginsto decrease and eventually enters a bradycardia zone 853-2, in which abradycardia response is observed in response to the stimulation signals.The low frequency of the stimulation signal in the second set 820 ofstimulation signals limits the functional effects of nerve fiberrecruitment and, as a result, the heart response remains relativelylimited. Although this low frequency stimulation results in minimal sideeffects, the stimulation intensity is too low to result in effectiverecruitment of nerve fibers and engagement of the autonomic nervoussystem. As a result, a therapeutic level of stimulation is notdelivered.

A third set of 830 of stimulation signals is delivered at a thirdfrequency higher than the first and second frequencies (e.g., 20 Hz). Aswith the first set 810 and second set 820, at lower intensities, thepatient first experiences a tachycardia zone 851-3. At this higherfrequency, the level of increased heart rate is undesirable. As theintensity is further increased, the heart rate decreases, similar to thedecrease at the first and second frequencies but at a much higher rate.The patient first enters the neural fulcrum zone 852-3 and then theundesirable bradycardia zone 853-3. Because the slope of the curve forthe third set 830 is much steeper than the second set 820, the region inwhich the patient's heart rate response is between 0% and −5% (e.g., theneural fulcrum zone 852-3) is much narrower than the neural fulcrum zone852-2 for the second set 820. Accordingly, when testing differentoperational parameter settings for a patient by increasing the outputcurrent amplitude by incremental steps, it can be more difficult tolocate an amplitude in the neural fulcrum zone 852-3. It is likely thatthe patient will traverse from the tachycardia zone 851-3 to theundesirable bradycardia zone 853-3 in a single step. At that point, theclinician would need to reduce the amplitude by a smaller increment inorder to produce the desired heart rate response for the neural fulcrumzone 852-3.

FIG. 8C is a chart 880 illustrating mean heart rate response surfaces inconscious, normal dogs during 14 second periods of right cervical vagusVNS stimulation ON-time. The heart rate responses shown in z-axisrepresent the percentage heart rate change from the baseline heart rateat various sets of VNS parameters, with the pulse width the pulse widthset at 250 μsec, the pulse amplitude ranging from 0 mA to 3.5 mA(provided by the x-axis) and the pulse frequency ranging from 2 Hz to 20Hz (provided by the y-axis). Curve 890 roughly represents the range ofstimulation amplitude and frequency parameters at which a null response(i.e., 0% heart rate change from baseline) is produced. This nullresponse curve 890 is characterized by the opposition of functionalresponses (e.g., tachycardia and bradycardia) arising from afferent andefferent activation.

FIG. 9 illustrates a method of operating an implantable medical device(IMD) comprising neurostimulator coupled to an electrode assembly. Thismethod can be implemented using, for example, the VNS systems describedabove.

In step 901, the IMD is activated to deliver to the patient a pluralityof stimulation signals at a first frequency (e.g., 2 Hz, as describedabove with respect to FIG. 9). Each of the plurality of stimulationsignals is delivered having at least one operational parameter settingdifferent than the other stimulation signals. For example, as describedabove, the output current amplitude is gradually increased whilemaintaining a fixed frequency. In other embodiments, differentparameters may be adjusted to increase the intensity of stimulation at afixed frequency.

In step 902, the patient's physiological response is monitored. In theexample described above with respect to FIG. 8, the physiologicalresponse being observed is the patient's basal heart rate duringstimulation at the various intensities at the first frequency. Thephysiological response may be measured using an implanted or externalphysiological sensor, such as, e.g., an implanted heart rate monitor 31,as well as other available physiological data, for instance, asderivable from an endocardial electrogram.

In step 903, the neural fulcrum zone for that first frequency isidentified. In the example described above with respect to FIG. 8, theneural fulcrum zone corresponds to the range of stimulation parametersettings that result in a heart rate change of about 0% to about adecrease of 5%. In other embodiments, a different range of target heartrate changes or other physiological responses may be used to identifythe neural fulcrum zone.

In accordance with some embodiments, stimulation at multiple frequenciesmay be delivered to the patient. In step 904, the IMD is activated todeliver to the patient a plurality of stimulation signals at a secondfrequency. In step 905, the patient's physiological response (e.g.,basal heart rate) at the second frequency is observed. In step 906, theneural fulcrum zone for the second frequency is identified. Additionalfrequencies may be delivered and corresponding neural fulcrum zones maybe identified for those frequencies.

As described in the various embodiments above, neural fulcrum zones maybe identified for a patient. Different neural fulcrum zones may beidentified using different stimulation signal characteristics. Based onthe signal characteristics, the patient's physiological response to thestimulation may be mild with a low slope, as with, for example, thefirst set of stimulation signals 810 at a low frequency, or may beextreme with a large slope, as with, for example, the third set ofstimulation signals 830 at a high frequency. Accordingly, it may beadvantageous to identify a frequency at which the reaction is moderate,producing a moderate slope corresponding to a wide neural fulcrum zonein which therapeutically effective stimulation may be provided to thepatient.

The observation of tachycardia in the tachycardia zone 851-2 andbradycardia in the bradycardia zone 853-2 indicates that the stimulationis engaging the autonomic nervous system, which suggests that atherapeutically effective intensity is being delivered. Typically,clinicians have assumed that stimulation must be delivered at intensitylevels where a significant physiological response is detected. However,by selecting an operational parameter set in the neural fulcrum zone852-2 that lies between the tachycardia 851-2 and the bradycardia zone853-2, the autonomic nervous system may still be engaged without riskingthe dangers of either tachycardia or bradycardia. At certain lowfrequencies, the bradycardia zone may not be present, in which case theneural fulcrum zone 852-2 is located adjacent to the tachycardia zone.While providing stimulation in the neural fulcrum zone, the autonomicnervous system remains engaged, but the afferent and efferent activationare at sufficient balance that the heart rate response is minimized.Ongoing stimulation therapy may then be delivered to the patient at afixed intensity within the neural fulcrum zone.

Fine Control of Neurostimulation

In accordance with embodiments of the present invention, fine control ofneurostimulation intensity settings may be achieved for locating theneural fulcrum zone. A patient's physiological response to stimulationmay vary depending on stimulation frequency and other stimulationparameters, and may be monitored by a clinician as a parameterindicative of the patient's autonomic balance. In accordance withembodiments of the present invention, one physiological responseindicative of autonomic balance is a heart rate response.

In the embodiment shown in FIG. 8B, the patient's varying heart rateresponse to stimulation at different stimulation frequencies is shown.At low stimulation frequencies, such as the 5 Hz frequency correspondingto the second set 820 of stimulation signals in FIG. 8B, the slope ofthe heart rate response curve is very low, and a step change instimulation intensity results in a small change in cardiac response. Incontrast, at high stimulation frequencies, such as the 20 Hz frequencycorresponding to the third set of 830 of stimulation signals in FIG. 8B,the slope of the heart rate response curve is large, particularly in theneural fulcrum zone 852-3, and a step change in stimulation intensityresults in a large change in cardiac response. In accordance withembodiments of the present invention, an understanding of therelationship between the neural fulcrum zone and the stimulationparameters may be used to enable fine control of intensity settings whenattempting to locate the neural fulcrum zone.

FIG. 10 is an illustrative chart reflecting a heart rate response togradually increased stimulation intensity delivered by an implanted VNSsystem at two different frequencies. In this simplified example, theintensity setting along the x-axis comprises the stimulation outputcurrent, a first set 1010 of stimulation signals is delivered at a firstfrequency (e.g., 20 Hz), and a second set 1020 of stimulation signals isdelivered at a second frequency (e.g., 10 Hz).

In various embodiments, the various stimulation parameter settings forthe VNS system are adjusted according to predefined increments. In theexample shown in FIG. 10, adjustments to the stimulation output currentare made in 0.5 mA increments. In other cases, the adjustments to thestimulation output current may be made in different increments, such as,for example, 0.25 mA or 1.0 mA. In some cases, these predefinedincrements may be dictated by hardware or software limitations, such asa VNS pulse generator that can only be adjusted in 0.5 mA increments. Inother cases, the predefined increments may be imposed by themanufacturer or the clinician to improve consistency, simplicity, oradministrative ease.

If the VNS system were used to deliver a continuous range of outputcurrents at the first and second frequencies, the continuous heart rateresponse curves 1010 and 1020 shown in FIG. 10 would be detected.However, in accordance with embodiments of the present invention, theVNS system is configured to deliver stimulation output currents atpredetermined increments of 0.5 mA. As a result, when a first set 1010of stimulation signals is delivered at 20 Hz, four points along theheart rate response curve are detected: 1012-1, 1012-2, 1012-3, and1012-4. The heart rate responses at 1012-1, 1012-2, and 1012-3 detectedat the first three current levels (0.5 mA, 1.0 mA, and 1.5 mA) all fallwithin the tachycardia zone 851-1 for the first frequency. When theoutput current is increased by the predetermined increment of 0.5 mA,the next detected heart rate response at 1012-4 falls in the bradycardiazone 853-1. Because of the steep slope of the heart rate response curvein the neural fulcrum zone 852-1, when increasing the output current bythe predefined 0.5 mA increment, a heart rate response in the neuralfulcrum zone 852-2 is not detected.

When attempting to locate the neural fulcrum for a particular patient,if the detected heart rate response transitions from the tachycardiazone 851-1 to the bradycardia zone 853-1 in response to a singleincrement increase of the intensity setting, it may be desirable to usea different stimulation frequency to locate the neural fulcrum.Accordingly, the stimulation frequency is decreased (e.g., to 10 Hz, asshown in FIG. 10), and a second set 1020 of stimulation signals aredelivered to the patient at the lower frequency. As with the first set1010, the intensity of the stimulation is increased by predefinedincrements (e.g., of 0.5 mA) to provide heart rate response points1022-1, 1022-2, 1022-3, and 1022-4. Unlike the first set 1010, the heartrate response curve for the second frequency has a lower slope, whichprovides a clinician with a finer resolution investigation of the heartrate response curve in the neural fulcrum zone 852-2, even when limitedby the same 0.5 mA predefined increment of output current. As shown inFIG. 10, the first two stimulation signals at 0.5 mA and 1.0 mA resultin heart rate response points 1022-1 and 1022-2, respectively, whichfall within the tachycardia zone 851-2. Increasing the output current to1.5 mA results in heart rate response point 1022-3, which falls squarelywithin the neural fulcrum zone 852-2. If the output current is increasedby another predefined increment to 2.0 mA, a heart rate response point1022-4 falling within the bradycardia zone 853-1 is detected.

As a result, a clinician may determine that the stimulation parametersettings resulting in the heart rate response point 1022-3 correspondsto the neural fulcrum zone. Accordingly, the VNS system may beconfigured to chronically deliver stimulation signals corresponding tothe identified neural fulcrum zone to treat chronic cardiac dysfunction.

In some situations, such as that illustrated in the second set 820 ofstimulation signals of FIG. 8B, the stimulation frequency may be so lowthat stimulation signal limits the functional effects of nerve fiberrecruitment, and the heart rate response remains relatively limited.Although this low frequency stimulation results in minimal side effectsand never induces bradycardia, despite increases in the output current,the overall stimulation intensity remains too low to result in effectiverecruitment of nerve fibers and engagement of the autonomic nervoussystem. As a result, a therapeutic level of stimulation is notdelivered. This is illustrated in FIG. 8B by the low slope of the heartrate response to the second set 820 of stimulation signals. Despiteincreases in the output current up to maximum levels tolerable by thepatient, the stimulation signals never reach the level of autonomicengagement.

In accordance with embodiments of the present invention, if incrementalincreases of an intensity setting (e.g., output current) at a firstfrequency do not result in an adequate change in the heart rate, thefrequency of stimulation may be increased to produce a heart rateresponse curve with a larger slope. The output current may be reduced toan initial level (e.g., 0.5 mA), with subsequent stimulation signalsdelivered at incrementally increasing output currents. Aftertransitioning past the tachycardia zone, a stimulation signal deliveredat the higher frequency at one output current level will induce a heartrate response point that falls within the neural fulcrum zone, and asubsequent stimulation signal with a single predefined incrementalincrease in the output current level induces a heart rate response inthe bradycardia zone. The output current level may then be reduced bythe predefined increment to bring the stimulation back into the neuralfulcrum zone.

It will be understood that output current is merely one example of astimulation parameter that may be adjusted in order to identify theneural fulcrum zone. In other embodiments, the stimulation may be variedby adjusting the other intensity parameters, such as, for example, pulsewidth and duty cycle.

In various embodiments described above, the patient's heart rateresponse is used as the patient parameter indicative of the patient'sautonomic balance in response to the stimulation for locating the neuralfulcrum zone. In other embodiments, different patient parameters may bemonitored in conjunction with stimulation, including, for example, otherheart rate variability parameters, ECG parameters such as PR intervaland QT interval, and non-cardiac parameters such as respiratory rate andskin conductance. Increases and decreases in these patient parameters inresponse to changes in stimulation intensity may be used to identify thepatient's neural fulcrum. If the change in the patient parameter inresponse to an incremental increase in a stimulation parameter is toolarge to enable identification of the neural fulcrum zone (e.g., theslope of the response curve is large), the frequency of the stimulationmay be decreased and an additional set of stimulation signals may bedelivered to the patient. At the lower frequency, the slope of theresponse curve will decrease, enabling a finer resolution identificationof the neural fulcrum zone. Conversely, if the change in the patientparameter is too low (e.g., the slope of the response curve is toosmall), the frequency may be increased in order to achieve finerresolution identification of the neural fulcrum zone.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope. Forexample, in various embodiments described above, the stimulation isapplied to the vagus nerve. Alternatively, spinal cord stimulation (SCS)may be used in place of or in addition to vagus nerve stimulation forthe above-described therapies. SCS may utilize stimulating electrodesimplanted in the epidural space, an electrical pulse generator implantedin the lower abdominal area or gluteal region, and conducting wirescoupling the stimulating electrodes to the generator.

What is claimed is:
 1. A method of operating an implantable medical device (IMD) comprising a neurostimulator coupled to an electrode assembly, said neurostimulator adapted to deliver a stimulation signal at a plurality of intensity parameter levels at predefined increments, said method comprising: monitoring a heart rate of a patient implanted with the IMD; delivering to the patient a first set of stimulation signals at a first frequency, wherein said delivering comprises incrementally increasing the intensity parameter level by the predefined increment for subsequent stimulation signals until bradycardia is detected; detecting tachycardia or a transition heart rate response in response to the stimulation signal having a first intensity parameter level one predefined increment below a second intensity parameter level at which bradycardia is detected; based on detecting tachycardia in response to the stimulation signal having the first intensity parameter level, delivering to the patient a second set of stimulation signals at a second frequency lower than the first frequency, wherein said delivering the second set of stimulation signals comprises incrementally increasing the intensity parameter level by the predefined increment for subsequent stimulation signals until bradycardia is detected; and based on detecting the transition heart rate response in response to the stimulation signal having the first intensity parameter level, identifying the stimulation signal resulting in the transition heart rate response as corresponding to a neural fulcrum zone.
 2. The method according to claim 1, further comprising: activating the IMD to chronically deliver stimulation signals corresponding to the identified neural fulcrum zone.
 3. The method according to claim 2, wherein said activating the IMD to chronically deliver stimulation signals comprises activating the IMD to chronically deliver stimulation signals corresponding the identified neural fulcrum zone to treat chronic cardiac dysfunction.
 4. The method according to claim 1, wherein: said intensity parameter level comprises an output current; and said delivering the first set of stimulation signals comprises incrementally increasing the output current by the predefined increment for subsequent stimulation signals until bradycardia is detected.
 5. The method according to claim 4, wherein: said predefined increment comprises approximately 0.25 mA; and said incrementally increasing the output current by the predefined increment comprises incrementally increasing the output current by 0.5 mA for subsequent stimulation signals until bradycardia is detected.
 6. The method according to claim 1, wherein: said first frequency comprises approximately 10 Hz.
 7. The method according to claim 6, wherein: said second frequency comprises approximately 5 Hz.
 8. The method according to claim 1, wherein: the transition heart rate response comprises a heart rate change of between 0% and 5% reduced heart rate.
 9. The method according to claim 1, wherein: said intensity parameter level comprises a pulse width or duty cycle.
 10. The method according to claim 1, further comprising: prior to delivering the first set of stimulation signals, completing a titration process in which stimulation intensity is gradually increased over a period of time to adapt the patient to the stimulation.
 11. The method according to claim 1, wherein said IMD is adapted to deliver the stimulation signals to a vagus nerve of the patient.
 12. The method according to claim 1, wherein: in the second set of stimulation signals if tachycardia is detected in response to the stimulation signal having the first intensity parameter level, delivering to the patient a third set of stimulation signals at a third frequency lower than the second frequency, wherein said delivering the third set of stimulation signals comprises incrementally increasing the intensity parameter level by the predefined increment for subsequent stimulation signals until bradycardia is detected.
 13. A method of operating an implantable medical device (IMD) comprising a neurostimulator coupled to an electrode assembly, said neurostimulator adapted to deliver a stimulation signal at a plurality of intensity parameter levels at predefined increments, said method comprising: monitoring a heart rate of a patient implanted with the IMD; delivering to the patient a first set of stimulation signals at a first frequency, wherein said delivering comprises incrementally increasing the intensity parameter level by the predefined increment for subsequent stimulation signals until either bradycardia or a transition heart rate response is detected; detecting tachycardia or a transition heart rate response in response to the stimulation signal having a first intensity parameter level one predefined increment below a second intensity parameter level at which bradycardia is detected; based on detecting tachycardia in response to the stimulation signal having the first intensity parameter level, delivering to the patient a second set of stimulation signals at a second frequency lower than the first frequency, wherein said delivering the second set of stimulation signals comprises incrementally increasing the intensity parameter level by the predefined increment until either bradycardia or a transition heart rate response is detected; and based on detecting the transition heart rate response in response to the stimulation signal having the first intensity parameter level, identifying the stimulation signal resulting in the transition heart rate response as corresponding to a neural fulcrum zone.
 14. The method according to claim 13, further comprising: activating the IMD to chronically deliver stimulation signals corresponding to the identified neural fulcrum zone.
 15. The method according to claim 14, wherein said activating the IMD to chronically deliver stimulation signals comprises activating the IMD to chronically deliver stimulation signals corresponding the identified neural fulcrum zone to treat chronic cardiac dysfunction.
 16. The method according to claim 13, wherein: said intensity parameter level comprises an output current; and said delivering the first set of stimulation signals comprises incrementally increasing the output current by the predefined increment for subsequent stimulation signals until bradycardia is detected.
 17. The method according to claim 16, wherein: said predefined increment comprises approximately 0.5 mA; and said incrementally increasing the output current by the predefined increment comprises incrementally increasing the output current by 0.5 mA for subsequent stimulation signals until bradycardia is detected.
 18. The method according to claim 13, wherein: said first frequency comprises approximately 10 Hz.
 19. The method according to claim 18, wherein: said second frequency comprises approximately 5 Hz.
 20. The method according to claim 13, wherein: the transition heart rate response comprises a heart rate change of between 0% and 5% reduced heart rate.
 21. The method according to claim 13, wherein: said intensity parameter level comprises a pulse width or duty cycle.
 22. The method according to claim 13, further comprising: prior to delivering the first set of stimulation signals, completing a titration process in which stimulation intensity is gradually increased over a period of time to adapt the patient to the stimulation.
 23. The method according to claim 13, wherein said IMD is adapted to deliver the stimulation signals to a vagus nerve of the patient.
 24. A neurostimulation system, comprising: an implantable medical device (IMD) comprising a neurostimulator coupled to an electrode assembly, said neurostimulator adapted to deliver a stimulation signal to a patient; and a control system programmed to: monitor a heart rate of a patient implanted with the IMD; activate the IMD to deliver to the patient a first set of stimulation signals at a first frequency, wherein said delivery comprises incrementally increasing the intensity parameter level by the predefined increment for subsequent stimulation signals until bradycardia is detected; detect tachycardia or a transition heart rate response in response to the stimulation signal having a first intensity parameter level one predefined increment below a second intensity parameter level at which bradycardia is detected; activate the IMD, based on detection of tachycardia in response to the stimulation signal having the first intensity parameter level, to deliver to the patient a second set of stimulation signals at a second frequency lower than the first frequency, wherein said delivery of the second set of stimulation signals comprises incrementally increasing the intensity parameter level by the predefined increment for subsequent stimulation signals until bradycardia is detected; and identify, based on the detection of the transition heart rate response in response to the stimulation signal having the first intensity parameter, the stimulation signal resulting in the transition heart rate response as corresponding to a neural fulcrum zone.
 25. The system according to claim 24, wherein the control system is further programmed to activate the IMD to chronically deliver stimulation signals corresponding to the identified neural fulcrum zone.
 26. The system according to claim 25, wherein the control system is programmed to activate the IMD to chronically deliver stimulation signals corresponding to the identified neural fulcrum zone to treat chronic cardiac dysfunction.
 27. The system according to claim 24, wherein said intensity parameter level comprises an output current.
 28. The system according to claim 27, wherein said predefined increment comprises approximately 0.5 mA.
 29. The system according to claim 24, wherein: the transition heart rate response comprises a heart rate change of between 0% and 5% reduced heart rate.
 30. A system according to claim 24, wherein: said IMD is adapted to deliver the stimulation signal to a vagus nerve of the patient. 